SELECTIVE ACTION OF CYTOCHALASIN A AS A RESPIRATORY INHIBITOR IN BACTERIA AND FUNGI.

The effect of cytochalasins, a group of fungal metabolites, on the respiration of bacteria and fungi was investigated. Among several cytochalasins used only cytochalasin A (CA), a thiol-blocking reagent, inhibited respiration of certain bacteria and fungi at low concentrations. Thirteen bacterial species (5 gram positives and 8 gram negatives) were tested for CA-inhibition of respiration. All the gram negative organisms used were CA-resistant whereas the gram positive organisms were susceptible. The CA-inhibition of respiration in gram positive bacteria was rapid, concentration dependent and generally reversible by washing, except in Bacillus subtilis, and not mediated via inhibition of substrate transport. The CA-susceptibility of bacteria was related to their permeability to this compound. Gram negative organisms which were resistant had low CA-permeability whereas susceptible gram positive organisms possessed high permeability. CA-resistant gram negative bacteria became CA-susceptible and CA-permeable when their permeability was modified with EDTA-treatment. Among various fungi from 6 phylogenetic groups examined only Oomycetes and Chytridiomycetes were susceptible to CA-inhibition of respiration. Except in Basidiomycetes CA-susceptibility was correlated with CA-permeation into the cells. Experiments with Achlya ambisexualis, a typical Oomycetous fungus, indicated that CA-inhibition of respiration in this fungus was rapid, concentration dependent, irreversible and not mediated by inhibition of substrate transport. Although Achlya mitochondria in vitro respired the TCA-cycle intermediates pyruvate, alpha-ketoglutarate and succinate with good acceptor control ratios, CA inhibited only pyruvate oxidation. In contrast to the irreversible CA-action in intact systems, inhibition of pyruvate oxidation by isolated mitochondria was reversible by washing. Both in bacteria and in fungi CA acts as a thiol-blocking reagent. This thiol-blocking property of CA is the key to its effectiveness as a respiratory inhibitor. The selective action of CA as a respiratory inhibitor is mainly responsible for its bacteriostatic and fungistatic properties in susceptible organisms.Dept. of Biological Sciences. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis1981 .M252. Source: Dissertation Abstracts International, Volume: 42-03, Section: B, page: 0917. Thesis (Ph.D.)--University of Windsor (Canada), 1981

Efficacy of voriconazole plus amphotericin B or micafungin in a guinea-pig model of invasive pulmonary aspergillosis

ABSTRACTThe efficacy of voriconazole in combination with amphotericin B or micafungin was studied in a transiently neutropenic guinea-pig model of invasive pulmonary aspergillosis. Guinea-pigs treated with the antifungal drugs, alone or in two-drug combinations, had an improved survival rate and reduced fungal burden in the lungs compared to untreated control animals. The efficacy of monotherapy and combination therapy was similar; activity was neither enhanced nor reduced with the two-drug combinations. Further studies of efficacy, dosing and optimal regimens for antifungal combinations are warranted

The effects of cytochalasin A on spore germination and growth of the water mold Achlya ambisexualis.

Dept. of Biological Sciences. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis1977 .M235. Source: Masters Abstracts International, Volume: 40-07, page: . Thesis (M.Sc.)--University of Windsor (Canada), 1977

Synthesis and evaluation of novel antifungal agents targeted to the plasma membrane H[+]-ATPase

A library of dienones were synthesized as candidate antifungal agents. These compounds were screened against Saccharomyces cerevisiae and Candida albicans using macro-broth susceptibility assay. The dienones exhibited a broad range of inhibition against S. cerevisiae (0.2-99%) and C. albicans (0-99%). 3,5-bis(p- trifluoromethylbenzylidene)-1-methyl-piperidine-4-one was identified as the most potent inhibitor of S. cerevisiae. Whereas, the most promising inhibitor of C. albicans was 2,6-bis(pyridine-3ylmethylene)cyclohexan-1-one

3-(4-Chloro­benzo­yl)-4-(4-chloro­phen­yl)-1-phenethyl­piperidin-4-ol

In the title compound, C26H25Cl2NO2, the piperidine ring adopts a chair conformation with a cis configuration of the carbonyl and hy­droxy substituents. The dihedral angle between the aromatic rings of the chloro­benzene groups is 24.3 (2)°. The phenyl ring forms dihedral angles of 59.4 (3) and 44.1 (3)° with the benzene rings. In the crystal, mol­ecules are linked by inter­molecular O—H⋯N and C—H⋯O hydrogen bonds and C—H⋯π inter­actions into layers parallel to the bc plane

The Mechanism of Antifungal Action of Essential Oil from Dill (Anethum graveolens L.) on Aspergillus flavus

The essential oil extracted from the seeds of dill (Anethum graveolens L.) was demonstrated in this study as a potential source of an eco-friendly antifungal agent. To elucidate the mechanism of the antifungal action further, the effect of the essential oil on the plasma membrane and mitochondria of Aspergillus flavus was investigated. The lesion in the plasma membrane was detected through flow cytometry and further verified through the inhibition of ergosterol synthesis. The essential oil caused morphological changes in the cells of A. flavus and a reduction in the ergosterol quantity. Moreover, mitochondrial membrane potential (MMP), acidification of external medium, and mitochondrial ATPase and dehydrogenase activities were detected. The reactive oxygen species (ROS) accumulation was also examined through fluorometric assay. Exposure to dill oil resulted in an elevation of MMP, and in the suppression of the glucose-induced decrease in external pH at 4 µl/ml. Decreased ATPase and dehydrogenase activities in A. flavus cells were also observed in a dose-dependent manner. The above dysfunctions of the mitochondria caused ROS accumulation in A. flavus. A reduction in cell viability was prevented through the addition of L-cysteine, which indicates that ROS is an important mediator of the antifungal action of dill oil. In summary, the antifungal activity of dill oil results from its ability to disrupt the permeability barrier of the plasma membrane and from the mitochondrial dysfunction-induced ROS accumulation in A. flavus

Target protection as a key antibiotic resistance mechanism

Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways